Clinical pathological correlations for human genetic disorders affecting the nervous system are important for the logical and successful development of diagnostic techniques and therapeutic strategies. Gaucher disease, the most common sphingolipidosis, is extremely useful as a model because of the occurrence of both neuronopathic and non-neuronopathic phenotypes. Understanding the basis of the broad spectrum of clinical diversity within the major types of this disorder may provide insight into factors which contribute to phenotypic heterogeneity in other diseases. Phenotypic heterogeneity in Gaucher disease is studied both through clinical examination of diverse patient populations and by study of transgenic animal models created by gene targeting. The Gaucher mouse homozygous for null alleles has a devastating clinical course. It has aided in the recognition of a subgroup of type 2 Gaucher patients who die in the neonatal period. Both the Gaucher mice and neonatal patients have skin changes, substantiating the important role of glucocerebrosidase in the maturation of functionally normal skin. These skin changes only found in type 2 Gaucher patients and may provide a means to presymptomatically discriminate between Gaucher phenotypes. Studies are ongoing to attempt to correlate patient phenotype with DNA mutation, but in Gaucher disease there is significant genotypic heterogeneity among clinically similar patients, and it is thus still difficult to assign a clinical prognosis based solely upon PCR determined genotype. Molecular analysis of patients with unusual or severe clinical manifestations are providing valuable insights. Other factors including transcription, regulatory regions, activator proteins and nearby gene sequences including a pseudogene, and a newly discovered gene, metaxin, are being studied. The techniques and information obtained from the study of heterogeneity and gene expression in Gaucher disease should be useful for formulating strategies for recognizing and understanding the biochemical and genetic bases of other disorders affecting the nervous system.